Dedifferentiation precedes invasion in the progression from Barrett's metaplasia to esophageal adenocarcinoma
Dedifferentiation precedes invasion in the progression from Barrett's metaplasia to esophageal adenocarcinoma
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DOI：
10.1158/1078-0432.ccr-04-1280
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发表时间：
2005-04-01
影响因子：
11.5
通讯作者：
Yeatman, TJ
中科院分区：
文献类型：
--
作者：
Helm, J;Enkemann, SA;Yeatman, TJ
目的：腺癌发生于巴雷特食管，由化生发展为癌，通过发育不良分级。在这项探索性研究中，我们的目的是描述导致这种组织学进展为癌症的基因表达的广泛变化，并评估使用这些基因表达变化作为预测巴雷特上皮恶性进展的标志物的潜力。实验设计：采用微阵列分析获得9例食管腺癌和巴雷特上皮的内窥镜活检的个体基因表达谱，其中3例是由巴雷特上皮引起的。收集了6例无癌或非典型增生患者的巴雷特上皮样本作为参考。结果：发生癌症的Barrett’s上皮与对照Barrett’s上皮的差异主要是由于基因表达不足，其中许多基因在控制细胞分化中起作用，这些基因表达的变化甚至在那些没有发育不良的Barrett’s上皮中也发现了。每种癌症都与巴雷特上皮不同，巴雷特上皮主要是由基因的过度表达引起的，其中许多与组织重塑和侵袭性有关。没有可识别的巴雷特上皮的癌症与由巴雷特上皮引起的癌症不同，因为这些过度表达的基因数量更多。结论：从巴雷特上皮到癌症的组织学进展与基因表达变化的梯度增加有关，其特征是在组织学改变之前开始的控制分化的基因功能的早期丧失；随后，与重塑和侵袭性相关的基因功能增加。组织学进展与基因表达变化增加的相关性表明，巴雷特上皮活检中基因表达的变化可能作为肿瘤进展的标记物，可用于预测发生癌症的风险。
Purpose: Adenocarcinoma arises in Barrett's esophagus by progression from metaplasia to cancer through grades of dysplasia. Our aim in this exploratory study was to characterize the broad changes in gene expression that underlie this histologic progression to cancer and assess the potential for using these gene expression changes as a marker predictive of malignant progression in Barrett's epithelium.Experimental Design: Microarray analysis was used to obtain individual gene expression profiles from endoscopic biopsies of nine esophageal adenocarcinomas and the Barrett's epithelia from which three of the cancers had arisen. Pooled samples from the Barrett's epithelia of six patients without cancer or dysplasia served as a reference.Results: Barrett's epithelia from which cancer had arisen differed from the reference Barrett's epithelia primarily by underexpression of genes, many of which function in governing cell differentiation, These changes in gene expression were found even in those specimens of Barrett's epithelia from which cancer had arisen that lacked dysplasia. Each cancer differed from the Barrett's epithelium from which it had arisen primarily by an overexpression of genes, many of which were associated with tissue remodeling and invasiveness. Cancers without identifiable Barrett's epithelium differed from cancers that had arisen from a Barrett's epithelium by having an even greater number of these overexpressed genes.Conclusions: Histologic progression from Barrett's epithelium to cancer is associated with a gradient of increasing changes in gene expression characterized by an early loss of gene function governing differentiation that begins before histologic change; gain in function of genes related to remodeling and invasiveness follows later. This correlation of histologic progression with increasing changes in gene expression suggests that gene expression changes in biopsies taken from Barrett's epithelium potentially could serve as a marker for neoplastic progression that could be used to predict risk for developing cancer.